Polymer-drug conjugates: towards a novel approach for the treatment of endrocine-related cancer

The last decade has seen successful clinical application of polymer–protein conjugates (e.g. Oncaspar, Neulasta) and promising results in clinical trials with polymer–anticancer drug conjugates. This, together with the realisation that nanomedicines may play an important future role in cancer diagnosis and treatment, has increased interest in this emerging field. More than 10 anticancer conjugates have now entered clinical development. Phase I/II clinical trials involving N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-doxorubicin (PK1; FCE28068) showed a four- to fivefold reduction in anthracycline-related toxicity, and, despite cumulative doses up to 1680 mg/m2 (doxorubicin equivalent), no cardiotoxicity was observed. Antitumour activity in chemotherapy-resistant/refractory patients (including breast cancer) was also seen at doxorubicin doses of 80–320 mg/m2, consistent with tumour targeting by the enhanced permeability (EPR) effect. Hints, preclinical and clinical, that polymer anthracycline conjugation can bypass multidrug resistance (MDR) reinforce our hope that polymer drugs will prove useful in improving treatment of endocrine-related cancers. These promising early clinical results open the possibility of using the water-soluble polymers as platforms for delivery of a cocktail of pendant drugs. In particular, we have recently described the first conjugates to combine endocrine therapy and chemotherapy. Their markedly enhanced in vitro activity encourages further development of such novel, polymer-based combination therapies. This review briefly describes the current status of polymer therapeutics as anticancer agents, and discusses the opportunities for design of second-generation, polymer-based combination therapy, including the cocktail of agents that will be needed to treat resistant metastatic cancer.

Nutrient-limited toxin production and the dynamics of two phytoplankton in culture media: a mathematical model

In this paper we have proposed and analyzed a simple mathematical model consisting of four variables, viz., nutrient concentration, toxin producing phytoplankton (TPP), non-toxic phytoplankton (NTP), and toxin concentration. Limitation in the concentration of the extracellular nutrient has been incorporated as an environmental stress condition for the plankton population, and the liberation of toxic chemicals has been described by a monotonic function of extracellular nutrient. The model is analyzed and simulated to reproduce the experimental findings of Graneli and Johansson [Graneli, E., Johansson, N., 2003. Increase in the production of allelopathic Prymnesium parvum cells grown under N- or P-deficient conditions. Harmful Algae 2, 135–145]. The robustness of the numerical experiments are tested by a formal parameter sensitivity analysis. As the first theoretical model consistent with the experiment of Graneli and Johansson (2003), our results demonstrate that, when nutrient-deficient conditions are favorable for the TPP population to release toxic chemicals, the TPP species control the bloom of other phytoplankton species which are non-toxic. Consistent with the observations made by Graneli and Johansson (2003), our model overcomes the limitation of not incorporating the effect of nutrient-limited toxic production in several other models developed on plankton dynamics.

Hydrogen-bonded complexes and blends of poly(acrylic acid) and methylcellulose: nanoparticles and mucoadhesive films for Ocular Delivery of Riboflavin

Poly(acrylic acid) (PAA) and methylcellulose (MC) are able to form hydrogen-bonded interpolymer complexes (IPCs) in aqueous solutions. In this study, the complexation between PAA andMC is explored in dilute aqueous solutions under acidic conditions. The formation of stable nanoparticles is established,whose size and colloidal stability are greatly dependent on solution pH and polymers ratio in the mixture. Poly(acrylic acid) and methylcellulose are also used to prepare polymeric films by casting from aqueous solutions. It is established that uniform films can be prepared by casting from polymer mixture solutions at pH 3.4–4.5. At lower pHs (pH<3.0) the films have inhomogeneous morphology resulting from strong interpolymer complexation and precipitation of polycomplexes, whereas at higher pHs (pH 8.3) the polymers form fully immiscible blends because of the lack of interpolymer hydrogen-bonding. The PAA/MC films cast at pH 4 are shown to be non-irritant to mucosal surfaces. These films provide a platform for ocular formulation of riboflavin, a drug used for corneal crosslinking in the treatment of keratoconus. An in vitro release of riboflavin as well as an in vivo retention of the films on corneal surfaces can be controlled by adjusting PAA/MC ratio in the formulations.

Identification of potential drug targets in Salmonella Typhimurium using metabolic modelling and experimental validation

almonella enterica serovar Typhimurium is an established model organism for Gram-negative, intracellular pathogens. Owing to the rapid spread of resistance to antibiotics among this group of pathogens, new approaches to identify suitable target proteins are required. Based on the genome sequence of Salmonella Typhimurium and associated databases, a genome-scale metabolic model was constructed. Output was based on an experimental determination of the biomass of Salmonella when growing in glucose minimal medium. Linear programming was used to simulate variations in energy demand, while growing in glucose minimal medium. By grouping reactions with similar flux responses, a sub-network of 34 reactions responding to this variation was identified (the catabolic core). This network was used to identify sets of one and two reactions, that when removed from the genome-scale model interfered with energy and biomass generation. 11 such sets were found to be essential for the production of biomass precursors. Experimental investigation of 7 of these showed that knock-outs of the associated genes resulted in attenuated growth for 4 pairs of reactions, while 3 single reactions were shown to be essential for growth.

A laminated polymer film formulation for enteric delivery of live vaccine and probiotic bacteria

Live bacterial cells (LBC) are administered orally as attenuated vaccines, to deliver biopharmaceutical agents, and as probiotics to improve gastrointestinal health. However, LBC present unique formulation challenges and must survive gastrointestinal antimicrobial defenses including gastric acid after administration. We present a simple new formulation concept, termed Polymer Film Laminate (PFL). LBC are ambient dried onto cast acid-resistant enteric polymer films that are then laminated together to produce a solid oral dosage form. LBC of a model live bacterial vaccine and a probiotic were dried directly onto a cast film of enteric polymer. The effectiveness at protecting dried cells in a simulated gastric fluid (pH 2.0) depended on the composition of enteric polymer film used, with a blend of ethylcellulose plus Eudragit L100 55 providing greater protection from acid than Eudragit alone. However, although PFL made from blended polymers films completely released low molecular weight dye into intestinal conditions (pH 7.0), they failed to release LBC. In contrast, PFL made from Eudragit alone successfully protected dried probiotic or vaccine LBC from simulated gastric fluid for 2h, and subsequently released all viable cells within 60min of transfer into simulated intestinal fluid. Release kinetics could be controlled by modifying the lamination method.

Development and exploitation of a controlled vocabulary in support of climate modelling

There are three key components for developing a metadata system: a container structure laying out the key semantic issues of interest and their relationships; an extensible controlled vocabulary providing possible content; and tools to create and manipulate that content. While metadata systems must allow users to enter their own information, the use of a controlled vocabulary both imposes consistency of definition and ensures comparability of the objects described. Here we describe the controlled vocabulary (CV) and metadata creation tool built by the METAFOR project for use in the context of describing the climate models, simulations and experiments of the fifth Coupled Model Intercomparison Project (CMIP5). The CV and resulting tool chain introduced here is designed for extensibility and reuse and should find applicability in many more projects.

Enteric coated spheres produced by extrusion/spheronization provide effective gastric protection and efficient release of live therapeutic bacteria

We present a novel but simple enteric coated sphere formulation containing probiotic bacteria (Lactobacillus casei). Oral delivery of live bacterial cells (LBC) requires live cells to survive firstly manufacturing processes and secondly GI microbicidal defenses including gastric acid. We incorporated live L. casei directly in the granulation liquid, followed by granulation, extrusion, spheronization, drying and spray coating to produce dried live probiotic spheres. A blend of MCC, calcium-crosslinked alginate, and lactose was developed that gave improved live cell survival during manufacturing, and gave excellent protection from gastric acid plus rapid release in intestinal conditions. No significant loss of viability was observed in all steps except drying, which resulted in approximately 1 log loss of viable cells. Eudragit coating was used to protect dried live cells from acid, and microcrystalline cellulose (MCC) was combined with sodium alginate to achieve efficient sphere disintegration leading to rapid and complete bacterial cell release in intestinal conditions. Viability and release of L. casei was evaluated in vitro in simulated GI conditions. Uncoated spheres gave partial acid protection, but enteric coated spheres effectively protected dried probiotic LBC from acid for 2 h, and subsequently released all viable cells within 1h of transfer into simulated intestinal fluid.

Structural parameters of polyacrylamide hydrogels obtained by the Equilibrium Swelling Theory

In this paper, the synthesis and structural characterization of a series of polyacrylamide hydrogels with different degrees of reticulation are reported. Although the Equilibrium Swelling Theory was recognized as a simple and reliable tool for the determination of structural hydrogels network parameters like equilibrium degree of swelling, cross-link ratio and mesh size, this is the first application of this methodology for polyacrylamide hydrogels. By changing the total monomer content in the synthesis solution (%T) from 5 to 30%, at a fixed value of cross-linker content in the total monomer amount (%C) of 5%, the final parameter obtained, the mesh size, can be tuned from 2 to 0.3 nm. It was also possible to change the mesh size (0.19-0.35) by varying %C from 5 to 12% (at %T = 20%). Scanning Electron Microscopy images for the most different formulations are shown and corroborate data obtained from the theory. (c) 2008 Elsevier Ltd. All rights reserved.

Transport modelling: macro and micro simulation for the studied case of Funchal

The work done in this thesis attempts to demonstrate the importance of using models that can predict and represent the mobility of our society. To answer the proposed challenges two models were examined, the first corresponds to macro simulation with the intention of finding a solution to the frequency of the bus company Horários do Funchal, responsible for transport in the city of Funchal, and some surrounding areas. Where based on a simplified model of the city it was possible to increase the frequency of journeys getting an overall reduction in costs. The second model concerns the micro simulation of Avenida do Mar, where currently is being built a new roundabout (Praça da Autonomia), which connects with this avenue. Therefore it was proposed to study the impact on local traffic, and the implementation of new traffic lights for this purpose. Four possible situations in which was seen the possibility of increasing the number of lanes on the roundabout or the insertion of a bus lane were created. The results showed that having a roundabout with three lanes running is the best option because the waiting queues are minimal, and at environmental level this model will project fewer pollutants. Thus, this thesis presents two possible methods of urban planning. Transport modelling is an area that is under constant development, the global goal is to encourage more and more the use of these models, and as such it is important to have more people to devote themselves to studying new ways of addressing current problems, so that we can have more accurate models and increasing their credibility.